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Uterine Neoplasms

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Uterine Diseases

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Genital Diseases

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Female Urogenital Diseases and Pregnancy Complications

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Lenvatinib

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AdHER2DC vaccine + pembrolizumab + de-escalating doses of lenvatinib

AdHER2DC vaccine + N-803 + pembrolizumab + RP2D of lenvatinib

AdHER2DC vaccine is given by intradermal injections on Day 1 of cycles 1-3 (priming) followed by optional boost doses (up to 3), on Day 1 of cycles 6, 9, 12

AdHER2DC vaccine

Pembrolizumab is given by IV infusion on Day 8 of cycle 1 and Day 1 of cycles 2-16

N-803 is given by subcutaneous injections on Day 1 of cycles 1-16

N-803

Lenvatinib is taken orally on Days 8-28 on cycle 1 and every day of cycles 2-16

Used during screening to estimate eligibility

PATHWAY HER2 (4B5) assay

Hoyoung M Maeng, M.D.

Background:

Endometrial cancer (EC) of the uterus is becoming more common in the US. Sometimes EC often has increased levels of a protein called HER2. Cancers with HER2 tend to be more aggressive and have poorer outcomes.

Objective:

To test 2 study drugs-a vaccine that targets HER2 (AdHER2DC) plus a drug that supercharges immune cells that kill tumor cells (N-803)-combined with 2 FDA-approved cancer treatment drugs in people with EC.

Eligibility:

Adults aged 18 and older with HER2-positive EC that returned or got worse after treatment.

Design:

AdHER2DC vaccine is made from each participant s own blood. Participants will undergo apheresis: Blood is removed from the body through a tube attached to a needle. The blood passes through a machine that separates out the target cells. The remaining blood is returned to the body through a second needle. A special catheter may be needed.

The first treatment cycle is 28 days; each cycle after that will be 21 days.

All participants will get the 2 approved drugs and the vaccine. One drug is a tablet taken by mouth once a day, every day. The other drug is given through a tube attached to a needle inserted into a vein.

The vaccine is injected under the skin. Participants will receive the vaccine on day 1 of cycles 1, 2, and 3. Additional doses up to 3 doses will be give if possible.

Some participants will receive N-803. This drug is injected under the skin of the abdomen on day 1 of each cycle.

Treatment may last up to 1 year. Follow-up visits will continue up to 2 more years.

BACKGROUND:

* Endometrial cancer (EC) is the most common gynecologic cancer in the US and the incidence peaks around 50-60 years of age. 5-year overall survival in patients with metastasis is around 20 percent and treatment after the second-line treatment has not been effective for long-term control.
* Pembrolizumab is approved for microsatellite instability (MSI)-high endometrial cancer which is rare.
* Pembrolizumab and lenvatinib combination therapy as second-line therapy in patients with advanced or metastatic EC showed promising antitumor activity. Recently, the Food and Drug Administration (FDA) approved pembrolizumab and lenvatinib in patients with advanced endometrial cancer who received prior chemotherapy after decades of lapse in adding new treatment options with an improved progression free survival (PFS) 6.6 months (vs 3.8 months in standard care chemotherapy), overall response rate 30 percent and median duration of response of 9.2 months.
* HER2 is positive in 30 percent of endometrial cancer and anti-HER2 therapy has shown clinical benefit in metastatic EC. Trastuzumab is used off-label with chemotherapy and as maintenance.
* An autologous dendritic cell vaccine that is transduced with an adenoviral vector expressing extracellular domain and transmembrane domain of HER2 (AdHER2DC vaccine) was well tolerated and showed a preliminary clinical benefit of 33.3 percent among 21 evaluable patients (NCT01730118, total enrolled n=33). No cardiotoxicity was noted. Immunogenicity analysis in a limited number of patients suggested induction of both humoral and cellular immune responses.
* The combination of pembrolizumab and lenvatinib in EC showed antitumor activity with manageable toxicity but still showed the responses in a limited group of patients. To overcome the resistance to immune checkpoint inhibitors, the combination regimen to induce the antitumor immune response by the AdHER2 vaccine, control the negative immune regulators and hostile tumor microenvironment by vascular endothelial growth factor (VEGF) inhibitor lenvatinib, and an immune stimulatory cytokine IL-15 superagonist N-803 has the potential to make the tumor more responsive to the immunotherapy creating mutual synergy.

OBJECTIVES:

* Phase I: To estimate recommended Phase II dose (RP2D) of pembrolizumab, lenvatinib, N-803, and AdHER2DC vaccine in participants with HER2 positive endometrial cancer.
* Phase II: To preliminarily assess the efficacy of a combination of pembrolizumab, lenvatinib, N-803, and AdHER2DC vaccine in participants with HER2 positive endometrial cancer as determined by the proportion of participants without progression at 6 months.

ELIGIBILITY CRITERIA:

* Age \>=18 years.
* Metastatic or locally advanced endometrial cancer with HER2 immunohistochemistry (IHC) 1+, 2+ or 3+
* Progressed after at least 1 line of standard of care (SOC) systemic therapy Participants may have received any number of prior cytotoxic agents and no prior checkpoint inhibitors.
* ECOG performance status \<=2 and adequate organ function.

DESIGN:

* An open-label, two-arm, phase I/II study of pembrolizumab, lenvatinib, N-803, and AdHER2.
* During Phase I, we will estimate recommended Phase II dose (RP2D) of the lenvatinib in combination with AdHER2DC vaccine, pembrolizumab, and N-803.
* During Phase II we will continue to evaluate the safety and examine the efficacy of the study regimen at the RP2D of the lenvatinib in combination with AdHER2 DC vaccine, pembrolizumab, and N-803.
* Participants will undergo apheresis, and AdHER2DC vaccine will be generated by transducing the participants monocyte-derived dendritic cells with AdHER2 vector.
* Treatment will be delivered for up to 1 year or until progression or unacceptable toxicity.
* Up to 60 participants will be treated.

Pembrolizumab, Lenvatinib and IL-15 Superagonist N-803 in Combination With HER2 Targeting Autologous Dendritic Cell (AdHER2DC) Vaccine in Participants With Advanced or Metastatic Endometrial Cancer

Phase I/II Trial of Pembrolizumab, Lenvatinib and IL-15 Superagonist N-803 in Combination With HER2 Targeting Autologous Dendritic Cell (AdHER2DC) Vaccine in Participants With Advanced or Metastatic Endometrial Cancer (EC)

.All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGap.

Number of Dose Limiting Toxicities (DLT).

Defined as the time from the start of treatment to time of progression, death, or 6 months. The fraction who can be alive without progression at 6 months will be reported along with an 80% two-sided confidence interval (the lower bound is the one-sided 90% bound, which will be used to compare to an estimated 54-55% from the Makker 2022 result) and a 95% two-sided confidence interval.

For participants receiving 4 agents, their safety will be evaluated with respect to the grades and types of toxicities obtained. The results will be presented descriptively and tabled if appropriate.

Spots Global Cancer Trial Database for adher2dc vaccine